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ANTIFUNGAL THERAPY IN ANTIFUNGAL THERAPY IN FEBRILE NEUTROPENIC FEBRILE NEUTROPENIC

PATIENTS PATIENTS REVIEW OF TREATMENT REVIEW OF TREATMENT

CHOICESCHOICES AND STRATEGIES AND STRATEGIES

Jean KLASTERSKY, M.D., Ph. D.

Institut Jules Bordet, Brussels, Belgium

2G.S. MARTIN et al., NEJM 2003

3

Mc Neil M, CID 2001;13:;641-647

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Frequency of non-Aspergillus mould infections at Fred-Hutchinson Cancer Research Center (Seattle). The number of patients who developed proven or probable infection with Fusarium species, Zygomycetes and Scedosporium species from 1985 through 1999 are shown

0

2

4

6

8

10

12

14

16

1985-1989 1990-1994 1995-1999

Scedosporium speciesZygomycetesFusarium species

5

0

10

20

30

40

50

60

70

C.alb C.trop C.glab C.krus C.parap C.guil C.lusit other

Est OuestPathogenic Candida species in BMT recipients : Candida species that caused candidemia arecompared over 2 decades at the Fred Hutchinson Cancer Research Center. The incidence ofcandidemia decreased from 11.4 % in 1980-1986 (72) compared to 4.6 % after adoption offluconazole for prophylaxis (1984-1997).

Marr K & Bowden R, Transplant Infectious Diseases 1999;1:237-246.

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Antifungal prophylaxis in leukemia patients :

ECIL recommendations

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Comparative trials of antifungal agents in candidemia and invasive candidasis

Response rate Overall mortality

Fluconazole vs amphotericin B 70 % vs 79 % 33 % vs 40 %

Itraconazole vs amphotericin B 35 % vs 41 % 40 %

ABLC vs amphotericin B 63 % vs 68 % 41 % vs 39 %

Caspofungin vs amphotericin B 73 % vs 62 % 30 % vs 34 %

Voriconazole vs amphotericin B 41 % vs 41 % 36 % vs 42 %

Micafungin vs Ambisome 89 % vs 89 %

Anidulafungin vs fluconazole 75 % vs 60 % 26 % vs 31 %

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Why does the frequency of fungal infection increase ?

I.V. devices Immunosuppression Neutropenia Broad spectrum antibiotics Diabetes

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Rational for Empirical Antifungal Therapy inRational for Empirical Antifungal Therapy inNeutropenic Patients with Persistent FeverNeutropenic Patients with Persistent Fever

Early diagnosis of many fungal infections is difficult

Delayed treatment increasesmortality

Success of antibacterialempirical therapy

An Algorithm for Therapy of Febrile Neutropenia after Initial An Algorithm for Therapy of Febrile Neutropenia after Initial Empirical Therapy with Broad Spectrum AntibioticsEmpirical Therapy with Broad Spectrum Antibiotics

Follow Daily And Reassess After 72 Hours

Clinical response

Yes No

Pathogen isolated

Adjust to sensitivity

Look for localized infection

Use G/GM-CSF?

Continue for 7 days

Repeat cultures and serologyPerform chest CT and BAL

Add amphotericin, and possibly metronidazole, antivirals and/or G/GM-CSF as indicatedLook for non infectious causes of fever

Yes No

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Possible Causes of Persistent FeverPossible Causes of Persistent FeverApproximate Approximate frequency in frequency in high risk high risk patients (%)patients (%)

Fungal infections susceptible to empirical therapy 40

Fungal infections resistant to empirical antifungal therapy 5

Bacterial infections (with cryptic foci and resistant organisms) 10

Toxoplasma gondii, mycobacteria, or fastidious pathogens (legionella, mycoplasma, chlamydia, bartonella)

5

Viral infections (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, varicella-zoster virus, herpes simplex virus) and respiratory pathogens such as parainfluenza virus, respiratory syncytial virus, influenza viruses

5

Graft-versus-host-disease after hematopoietic stem-cell transplantation

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Undefined (e.g. drug fever, toxic effects of chemotherapy, antitumor responses, undefined pathogens)

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L. COREY and M. BOECKH, NEJM 2002

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13

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Infectious Complications in Each of the Groups Infectious Complications in Each of the Groups Following RandomizationFollowing Randomization

Randomization group

N°Clinically documented

Bacterial FungalViral Protozoal

Shock

Discontinue KGC 16 2 3 1 0 6

Continue KGC alone

16 0 1 5 0 0

KGC + Ampho B 18 0 0 1 1 0

P.A. PIZZO et al, Am J Med 1982KGC : cephalotin (Keflin), gentamicin, carbenicillin

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Clinical Response Clinical Response in Persistently (4 days) Febrile in Persistently (4 days) Febrile Neutropenic PatientsNeutropenic Patients

Ampho B No Ampho B p Value

Overall

All patients 55/80 (68) 39/77 (50) 0.10

Prior antifungal prophylaxis

No 21/27 (78) 9/20 (45) 0.04

Yes 19/31 (61) 24/39 (61) NS

Infection documentation

Clinical 22/29 (75) 14/31 (41) 0.03

Possible 25/39 (64) 20/33 (60) NS

Granulocyte count at Day 4

< 100/µL 31/45 (69) 20/43 (46) 0.06

100-500/µL 16/23 (70) 14/21 (67) NS

EORTC-IATCG, Am J Med 1989

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Causes of DeathCauses of Death with or without Empirical Ampho B with or without Empirical Ampho B in Persistently (4 Days) Febrile Neutropenic Patientsin Persistently (4 Days) Febrile Neutropenic Patients

Ampho B No Ampho B

Overall mortality (at day 30) * 11 14

Fungal infection** 0 4

Bacterial infection 1 2

Pulmonary infection (no bacterial or fungal pathogen identified at autopsy)

1 0

Other 9 8

(*) p = NS between the two groups(**) p = 0.05 between the two groups

EORTC-IATCG, Am J Med 1989

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Randomized Studies Comparing Empirical Treatment with Randomized Studies Comparing Empirical Treatment with Antifungal Agents for Persisting Fever during NeutropeniaAntifungal Agents for Persisting Fever during Neutropenia

YEAR STUDY ANTIFUNGAL AGENTS COMPARED

1982

1989

1996

1998

1998

1999

2000

2000

2001

2002

2004

Pizzo et al

EORTC

Viscoli et al.

Malik et al.

White et al..

Walsh et al.

Winston et al.

Wingard et al.

Boogaerts et al.

Walsh et al.

Walsh et al.

Conventional ampho B vs no antifungal therapy

Conventional ampho B vs no antifungal therapy

Conventional ampho B vs fluconazole

Conventional ampho B vs fluconazole

Conventional ampho B vs ampho B colloidal dispersion

Conventional ampho B vs liposomal ampho B

Conventional ampho B vs fluconazole

Liposomal ampho B vs ampho B lipid complex

Conventional ampho B vs itraconazole

Liposomal ampho B vs voriconazole

Liposomal ampho B vs caspofungin

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Measures of the Success (%) of Empirical Antifungal Therapy with Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Conventional or Liposomal Amphotericin B, Voriconazole or

CaspofunginCaspofungin

Ampho B Liposomal Ampho B Voriconazole Caspofungin (Ampho B) (Vori) (Caspo)

N° of patients 344 343 422 539 415 556

Overall success 49.4 50.1 30.6 33.7 26.0 33.9

Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2

No breakthroughfungal infection 89.2 90.1 95.0 95.5 98.1 94.8

Resolution ofbaseline infection 72.7 81.8 66.7 25.9 46.2 51.9

Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6

No discontinuationNo discontinuationfor toxic effectsfor toxic effects 81.481.4 85.7 93.4 85.5 85.7 93.4 85.5 90.1 89.7 90.1 89.7 or lack of efficacyor lack of efficacy

J. KLASTERSKY, NEJM 2004

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Comments on the Walsh’s studies

Large prospective controlled trials Composite score : « common language » BUT

– Survival and fever can be influenced by many other factors than just the nature of the empirical regimen

– What is the difference between « baseline » FI (<72h) and « breakthrough » FI (>72h) ?

– Discontinuation for toxicity or lack of efficacy :

« mixing apples and pears » ?

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Toxicity of Empirical Antifungal Therapy %

Conventional amphotericin

Liposomal amphotericin

Voriconazole Caspofungin

Total n° patients 344 1312 415 564

Chills

Nephrotoxicity*

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34

24

13

13

7

14

3

Discontinuation for toxicity

18 9 5** 5

* Creatinine increase 2 x base line ** Visual hallucinations more frequent with voriconazole (4.3 % vs 0.5 %)

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Measures of the Success (%) of Empirical Antifungal Therapy with Measures of the Success (%) of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole or Conventional or Liposomal Amphotericin B, Voriconazole or

CaspofunginCaspofungin Ampho B Liposomal Ampho B Voriconazole

Caspofungin (Ampho B) (Vorico) (Caspo)

N° of patients 344 343 422 539 415 556

Overall success 49.4 50.1 30.6 33.7 26.0 33.9

Resolution of fever 58.1 58.0 36.5 41.4 32.5 41.2

No breakthroughNo breakthroughfungal infectionfungal infection 89.2 90.1 95.0 95.5 89.2 90.1 95.0 95.5 98.1 98.1 94.8 94.8

Resolution ofResolution ofbaseline infectionbaseline infection 72.772.7 81.8 66.7 25.9 81.8 66.7 25.9 46.2 46.2 51.9 51.9

Survival for 7 day 89.5 92.7 94.1 89.2 92.0 92.6

No discontinuationfor toxic effects 81.4 85.7 93.4 85.5 90.1 89.7 or lack of efficacy

J. KLASTERSKY, NEJM 2004

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Cure of Base Line Fungal InfectionCure of Base Line Fungal Infection

Conventional ampho B

Liposomal ampho B

Voriconazole Caspofungin

Total n° of patients

344 961* 415 556

Response/n° (%)

8/11

(72.7)

20/44 (45.4)**

6/13

(46.2)

14/27

(51.9)

* 2 studies**Outcome in the study comparing conventional ampho B to liposomal ampho B was 9/11 (81.8)

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Choice of a suitable denominator for the evaluation of empirical therapy based on microbiological results

(T. Walsh) (J. Klastersky)

Success of therapy Failure of therapy

No breakthrough FI Total n° patients -

Cure of baseline FI N° of baseline FI -

Breakthrough FI - Total of n° of patients

No cure of baseline FI - Total of n° of patients

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Outcome of Empirical Antifungal Therapy in Outcome of Empirical Antifungal Therapy in Microbiologically Demonstrated Fungal InfectionsMicrobiologically Demonstrated Fungal Infections (FI) (FI)

Ampho B Liposomal ampho B

Voriconazole Caspofungin

(344) (961) (415) (556)

Breakthrough FI 37 (10.8) 45 (4.6) 8 (1.9) 29 (5.2)

No cure of base line FI 3 (0.8) 22 (2.2) 7 (1.6) 13 (2.3)

Total failures* 40 (11.6) 67 (6.9 %) 15 (3.6 %) 42 (7.7 %)

*p = 0.03

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Summary of trials of empirical antifungal therapy that evaluated alternatives to amphotericin B

Study drugs % of invasive fungal infections

n Arm 1 Arm 2 Arm 1 Arm 2

687 AmB L-Amb 8.7 5.0

384 AmB Itraconazole 2.7 2.7

837 L-AmB Voriconazole 5.0 1.9*

1095 L-AmB Caspofungin 4.3 5.2

* p< 0.5J.R. Wingard, CID, 2004

2626

27Aspergillus fumigatus

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Galatomannan detection for the diagnosis of Galatomannan detection for the diagnosis of invasive aspergillosisinvasive aspergillosis

Approved by FDA; standard : optical density index > 0.5 in 2 consecutive samples ?

Positivity can preceed radiological findings In probable or proven cases levels are often higher and

increase within days 81 % sensitivity; 89 % specificity; NPV:98 %; PPV:7-94 % False negatives : prophylactic use of mold-active

azoles, early antifungal therapy and others ? False positives : use of piperacillin-tazobactam and others ?

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AspergillusAspergillus Infections (AI) in Empirical Therapy Infections (AI) in Empirical Therapy

Liposomal ampho B

Voriconazole Caspofungin

(961) (415) (556)

Breakthrough AI 21 4 10

No cure of base line AI° 13* 4** 7

Total failures 24 (2.4 %) 8 (1.9 %) 17 (3.0 %)

° Assuming that 1/2 infections in the liposomal ampho B arm (*) and4/7 infections in the voriconazole arm (**) were caused by Aspergillus

31R. Herbrecht et al, N Engl J Med, 2002

32T.J. Walsh et al, N Engl J Med 2002 1.9 % 4.9 % (p = 0.02)

33T.J. Walsh et al, N Engl J Med 2004

34T.J.Walsh et al, N Engl J Med 2004

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12 CR 6 PR voriconazole 2 SD rescue12 No response (7 died < IFI) 8/12 : CR

36K.A. MARR et al, CID 2004

37N. Singh, Transplantation, 2006

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The prevalence of fungal infections in patients receiving empirical therapy is 4-8 %

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Prevalence of fungal infections in persistently neutropenic patients not receiving empirical therapy

Pizzo et al. (1982) 18

EORTC (1989) 28 *

Guiot et al. (1993) 26*

Corey and Boeckh (2002) 45

Maertens et al. (2005) 21

* Autopsy-based data

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41

CID, 2005

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The preemptive approach(adapted from Maertens et al.)

« Possible IFI »

Diagnostic evaluation for IFI

Reasons Procedures

. FN refractory for 5 days

. FUO relapsing after 48 h with N

. Signs or/and symptoms suggestive of IFI

. Isolation of molds/hypae in URT

. Galactomannan assays positive (> 0.5)

. HRCT of the chest (+ sinuses)

. Bronchoscopy +BAL - Smears + cultures for bacteria, fungi, mycobacteria, Legionella

- PCR for CMV, HSV, VZV, Toxoplasma, Pneumocystis, Mycoplasma, Chlamydia

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The preemptive approach(adapted from Maertens et al.)

« Possible IFI »

Liposomal amphotericin B (5 mg/kg)

IF– > 2 consecutives EIA for galactomannan assays

> 0.5)

OR– CT suggestive of IFI supported by microbiology

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The preemptive approach of persistent febrile neutropenia in 88 patients(adapted from Maertens et al.)

Persistent fever 35/117 (29 %) episodes Prevalence of IFI : 22 % (mortality 36 %) No aspergillar infection was missed Early therapy could be initiated in clinically not

suspected cases Significant (78 %) reduction in use of

antifungals

45CID, 2005

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Empirical versus preemptive therapy (liposomal amphotericin B) in patients with persisting fever

and neutropenia

Adapted from Maertens’ study 35 patients with persistent fever

EMPIRICAL APPROACH * PREEMPTIVE APPROACH

1 episode of IA (2.4 %) 10 episodes of IA (28 %)

? Death 2 deaths (20 %)

need of a controlled study

* Estimation from J. Klastersky, NEJM 2004

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Blood, 2006

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Empirical (E ) vs pre-emptive approach (PE)

Design

293 patients c hematological malignancies

R

Antifungal therapy

E

. Persistent or recurrent fever

PE

. Persistent or recurrent fever +. pneumonia. mucositis. septic shock. sinusitis. skin lesions. aspergillus colonisation. + gamacto-mannan

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Empirical (E ) vs pre-emptive approach (PE)

Results

E

150 patients

PE

143 patients

Diagnosed IFI 4 (2.6 %) 13 (9.0) p < 0.02

Overall survival 147 (98 %) 136 (95 %) NS

IFI related mortality 0 (0 %) 3 (2.1 %) p = 0.12

Mean cost (euros) 3595 3595 NS

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Estimated prevalence of invasive fungal infection (IFI) in neutropenic patients according to the management strategy

in exemplative studies

N° patients N° IFI Prevalence %

Controls ¹ 341 14 26.0

Prophylaxis ² (posaconazole)

291 7 2.4

Empirical therapy ³

(voriconazole)

415 15 3.6

Pre-emptive therapy (polyenes) 4

143 13 9.0

1 Guiot, CID, 19942 Ullmann, NEJM, 20073 Walsh, NEJM, 20024 Cordonnier, Blood, 2006

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Which Antifungal Drug is Best for the Which Antifungal Drug is Best for the Empirical Empirical Treatment of Treatment of Patients with Febrile Neutropenia?Patients with Febrile Neutropenia?

Few adverse effects

(amphotericin B < lipid preparations < voriconazole = caspo)

Superiority of action :

– conventional amphotericin looks to be the least effective

– voriconazole might be superior in reducing microbiologically proven

failures

– Cost

Resistance

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Average Daily Cost of Antifungal Therapy (Jules Bordet Bruxelles)

Dose Euros

Conventional Amphotericin B 1 mg/kg 8

Liposomal amphotericin B 3 mg/kg 629

Voriconazole 400 mg IV 407

Voriconazole 400 mg PO 84

Caspofungin 70 mg IV 644

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Sensitivity of common pathogenic fungi

Amphotericin B Voriconazole Caspofungin

Candida sp. S S S

C. lusitaniae R S S

C. krusei S S** S

C. glabrata S S** S

Trichosporon sp. R S S

Aspergillus sp.* S S S

Fusarium sp. R S R

Mucorales S R R

C. neoformans S S R

*Except terreus**MIC are higher than for C. albicans but still < 3 ng/ml

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Antifungal therapy in persistently febrile neutropenic patients

Voriconazole is presently the optimal choice for therapy and empirical therapy of suspected aspergillar infections

Early therapy (empirical) is needed since mortality remains high (30-50 %)

Empirical therapy reduces the incidence of IFI from + 25 % to + 3.5 %; the corresponding figures for liposomal ampho B and caspofungin being + 7 %

Experience with the preemptive approach is still limited; it is demanding in terms of diagnostic procedures but it reduces the rate of overtreatment.

There is evidence so far that pre-emptive therapy is inferior in efficacy and not more cost effective than the empirical approach

Conclusions

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Needs for Improvement Needs for Improvement of Neutropenic Febrile Patients with of Neutropenic Febrile Patients with Persistent Fever to Avoid OvertreatmentPersistent Fever to Avoid Overtreatment

1. Better diagnostic tools for EARLIER microbiological and

clinical diagnosis : galactomannan, PCR, those caused by

Aspergillus sp.

1. More accurate IDENTIFICATION OF PATIENTS at high

risk of fungal infections (cf MASCC score)

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Thank you foryour kind attention

and« Au revoir »